AXILLARY LYMPH NODE DISSECTION FOR PATIENTS WITH …
Transcript of AXILLARY LYMPH NODE DISSECTION FOR PATIENTS WITH …
AXILLARY LYMPH NODE DISSECTION FOR PATIENTS WITH INVASIVE BREAST CANCER AT CHARLOTTE MAXEKE JOHANNESBURG ACADEMIC HOSPITAL and CHRIS HANI BARAGWANATH ACADEMIC HOSPITAL
C Groenewald
W-01-01-06
A Research Report submitted to the Faculty of Health Science, University of
Witwatersrand, in fulfillment of the requirements for the degree of Masters in Surgery
(Mmed in Surgery)
Johannesburg 2019
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DECLARATION
I, Carolette Groenewald, declare that this Research Report is my own, unaided work.
Any assistance that I received is stated in my acknowledgements. It is being submitted
for the Degree of Mmed in Surgery at the University of the Witwatersrand,
Johannesburg. This report is being submitted in the format for a submissible paper.
It has not been previously submitted for any degree or examination at this or any other
University. This report does not utilise any previous or current work produced by another
individual.
I certify that the protocol has been approved by the Human Ethics Committee (Medical)
at the University of the Witwatersrand, Johannesburg (Appendix: Ethics Clearance
Certificate number M150549)
3/7/2019
Carolette Groenewald Date
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Dedicated to my husband, Renier Groenewald and the Penny family,
for your continuous love and support throughout this journey.
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PRESENTATIONS ARISING FROM THIS STUDY This publication’s abstract was presented at the meeting of the Surgical Research
Society of Southern Africa (SRS) in July 2017.
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ABSTRACT Background: The extent of axillary surgery correlates with its morbidity and sentinel
lymph node biopsy (SLNB) has become the standard of care in clinically node-negative
(cN0) breast cancer patients.
Objectives: This study aims to 1) evaluate the application of SLNB and axillary lymph
node dissection (ALND) and determine the prevalence of pathological node negative
(pN0) ALND’s and 2) determine the factors associated with pN0 ALND outcome in two
Johannesburg breast units.
Methods: We included female patients with primary breast cancer who underwent
axillary surgery in the breast units at Charlotte Maxeke Johannesburg Academic
Hospital (CMJAH) and Chris Hani Baragwanath Academic Hospital (CHBAH) from
March 2013 to March 2015. Univariate and multivariable logistic regression models were
used to determine factors associated with pN0 ALND.
Results: Five hundred and five patients were included and 344 patients (68.1%) were
staged clinically node-positive (cN1), 161 patients (31.9%) were assessed as cN0 and
deemed eligible for SLNB. Sensitivity of clinical nodal staging was 85.9% with a positive
predictive value (PPV) of 76.5%. The majority of patients (313, 61.9%) underwent
primary surgery while 192 patients (38.1%) underwent surgery after Neoadjuvant
chemotherapy (NACT). We performed 118 SLNBs and 387 ALNDs. There were 97 pN0
ALND’s and of all the SLNB’s and ALND’s, a total of 199 were pN0 tumours.
Risk was not increased after NACT (OR 1.06, p=0.790). We identified a significant risk
in patients with triple-negative and Human epidermal growth factor-2 (HER-2) enriched
subtypes compared to hormone receptor-positive patients (OR 3.05, 95% CI: 1.6-5.7,
p=0.001 and OR 2.25, 95% CI: 1.1-4.8, p=0.035).
Conclusions: The prevalence of pN0 ALND was 25.1%. Hormone receptor negative
tumours were associated with a higher pN0 ALND outcome as compared to luminal
cancers.
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Preoperative nodal assessment needs to be optimised and include pathological
confirmation. SLNB needs to be extended to patients after NACT despite resource-
constraints.
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ACKNOWLEDGMENTS I thank my supervisors Ms. Sarah Nietz, head of CMJAH Breast Unit and Mr .Herbert
Cubasch, head of CHBAH Breast Unit who allowed me to access the Breast Unit
databases and patient records. They also provided insight and expertise that greatly
assisted my research. You have cultivated a fondness and love for research in me.
I thank Tosin Ayeni for assistance with statistical analysis and the countless replies to
my middle of the night questions regarding the statistics.
I would also like to show our gratitude to the Prof Aylwyn Mannell for sharing her pearls
of wisdom with me during the course of this research
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TABLE OF CONTENTS DECLARATION.....................................................................................................................................................................IIPRESENTATIONSARISINGFROMTHISSTUDY........................................................................................................IVABSTRACT.............................................................................................................................................................................VACKNOWLEDGMENTS.....................................................................................................................................................VIITABLEOFCONTENTS....................................................................................................................................................VIIINOMENCLATURE...............................................................................................................................................................IXLISTOFFIGURES..................................................................................................................................................................XLISTOFTABLES.................................................................................................................................................................XICOVERLETTERTOTHEEDITOROFTHESAJS..............................................................................................................1. INTRODUCTION..........................................................................................................................................................12. METHODS.....................................................................................................................................................................33. RESULTS........................................................................................................................................................................54. DISCUSSION..............................................................................................................................................................11
5.CONCLUSION.............................................................................................................................................................13REFERENCES......................................................................................................................................................................15APPENDIXA–APPROVEDRESEARCHPROTOCOL................................................................................................19APPENDIXB–PROTOCOLASSESSMENTFORM......................................................................................................38APPENDIXC-ETHICSAPPROVAL...............................................................................................................................41APPENDIXD–SUPERVISORDECLARATION............................................................................................................42APPENDIXE-IDENTIFIABLEDATASHEET1.........................................................................................................43APPENDIXF–DATACOLLECTIONSHEET2.............................................................................................................44APPENDIXG–SAJSGUIDELINESTOAUTHORS......................................................................................................46
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NOMENCLATURE ALND - Axillary lymph node dissection
CHBAH - Chris Hani Baragwanath Academic Hospital
CMJAH - Charlotte Maxeke Johannesburg Academic Hospital
cN0 - Clinically node negative
cN1 - Clinically node positive
ER - Estrogen receptor
FNA - Fine needle aspiration
FNR - False negative rate
HER2 - Human epidermal growth factor receptor 2
NACT - Neoadjuvant chemotherapy
NCCN - National Comprehensive Cancer Network
NPV - Negative predictive value
OR - Odds ratio
pN0 - Pathological node-negative
pN+ - Pathological node-positive
PPV - Positive predictive value
PR - Progesterone receptor
SLNB - Sentinel lymph node biopsy
TNM -Tumour, Node and Metastasis
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LIST OF FIGURES Figure 1: Flowchart of axillary surgery
Figure 2: Flowchart of primary axillary surgery
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LIST OF TABLES Table 1 Demographic and clinicopathological characteristics
Table 2 Comparison of clinical and pathological nodal staging
Table 3 Validity of clinical staging and axillary surgery
Table 4 Univariate and multivariate analysis of factors associated with a pN0
ALND
Cover Letter to the Editor of the SAJS
23.12.2018
Dr. Carolette Groenewald University of the Witwatersrand Private Bag 3 Wits Johannesburg, South Africa 2050 +27835549670 [email protected]
Prof J Krige, Prof S Thomson - Editor-in-Chief South African Journal of Surgery Private Bag x1 Pinelands Cape Town South Africa 7700
Dear Professor Krige and Thomson
I am pleased to submit an original research article entitled “Axillary Lymph Node Surgery in
Breast Cancer: Saving the Axilla” by Carolette Groenewald, Sarah Nietz, Prof Alwyn Mannell,
Oluwatosin Ayeni and Herbert Cubasch for consideration for publication in the South African
Journal of Surgery.
We show that 25% of patients that are undergoing axillary lymph node dissection in our
practice have a pathologically node-negative dissection. Patients with hormone receptor-
negative breast cancer were at a higher risk compared to patients with receptor-positive
tumours. Neoadjuvant chemotherapy did not increase the risk. Omission of pre-operative
cytology or core biopsy of suspicious nodes showed a trend towards increased the risk but this
finding did not reach significance. Improvements in pre-operative clinical node assessment in
conjunction with a broader application of SLNB require consideration in our resource-
constrained environment to appropriately decrease the extent of axillary surgery in our
patients.
My co-authors and I would be grateful if you would read the enclosed paper and consider for
publication by South African Journal of Surgery as it is relevant to the South African context of
surgery.
This manuscript has not been published and is not under consideration for publication
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elsewhere. We have no conflicts of interest to disclose.
Thank you for your consideration.
Sincerely,
Dr. Carolette Groenewald
MBChB
Surgical Registrar, Department of General Surgery
Faculty of Health Sciences, University of the Witwatersrand
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1. INTRODUCTION The axillary lymph node status forms part of tumour staging and is an important
prognostic factor for patients with invasive breast cancer. 1 2 Methods to stage the axilla
include physical examination, dedicated imaging and histopathological confirmation.
Clinical evaluation of the axilla by palpation alone is relatively inaccurate and has a
reported sensitivity of 35%. 3 Axillary lymph nodes may appear clinically and
radiologically enlarged due to causes other than breast cancer. HIV infection is
commonly associated with benign axillary lymphadenopathy and recent data from
CHBAH showed that 19.7% of patients with breast cancer tested positive for HIV. 4
The term “clinically node-positive” has been redefined over the past years and in
current practice it usually entails pre-operative confirmation of positive nodal
involvement by cytology or core biopsy. In 2011 the results from a meta-analysis the
median sensitivity of ultrasound in detecting positive lymph node involvement in
patients with invasive breast cancer was found to be 61.4% and the specificity 82%,
these values increased further to 79.4% and 100% with the addition of ultrasound-
guided node biopsy. 5 In patients who appear cN1 due to palpable and/or
sonographically suspicious lymph nodes, fine needle aspiration (FNA) or core needle
biopsy of a suspicious lymph node can confirm nodal involvement and identify patients
who may proceed directly to ALND rather than SLNB. In cases where the FNA is
negative for nodal involvement the patient will undergo SLNB. 6 Unfortunately, we
could not confirm positive lymph node involvement by FNA or core biopsy or both in
our institutions, due to resource constraints. Patients who have palpable
lymphadenopathy or sonographically suspicious nodes proceed directly to ALND.
A first world medical centre performed an observational study on pN0 breast cancer
patients and found that 49% of patients ultimately underwent ALND either initially or
after SLNB.7 ALND carries morbidity and lymphoedema of the arm is the most frequent
long-term complication. 8 ALND have up to a 40% life time risk of developing
lymphoedema. 9 Since morbidities following ALND is directly related to the extent of
surgery, SLNB has become the standard of care in patients who have no nodal
involvement. ALND has no oncological benefit in node-negative patients and is thus
difficult to justify. 10
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An aspect that has been recently evolving is the use of SLNB following NACT. The
SLNB method has been adopted as an axilla-conserving option in the National
Comprehensive Cancer Network (NCCN) guidelines for patients who were initially cN1,
but who are down-staged following NACT to cN1 disease. 11 This was not adopted in
our practice at the time of this study.
In view of the general trend towards axilla-preservation, we audited the use of SLNB
and ALND in two breast units. Our study aimed to 1) evaluate the application of
SLNB and ALND and determine the prevalence of pN0 ALND’s, and 2) determine the
factors associated with an increased likelihood of pN0 ALND’s in two Johannesburg
breast units.
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2. METHODS Study population We performed a retrospective review at Charlotte Maxeke Johannesburg
Academic Hospital (CMJAH) and Chris Hani Baragwanath Academic Hospital
(CHBAH) Breast Units. Female patients who presented with primary invasive
breast cancer and who underwent axillary surgery from March 2013 to March
2015 were included. Patients were recruited via theatre and admission records
at CMJAH and via the electronic database at CHBAH. Exclusion criteria were
recurrent disease, the absence of invasive breast cancer, cases were breast
cancer was not the primary presentation and incomplete data.
Data were extracted from histology records, patient records via the breast files
at CMJAH and the database at CHBAH. Variables extracted included: site, age,
Tumour, Node and Metastasis (TNM) staging at presentation, preoperative
nodal staging as determined by physical examination and/or ultrasound,
preoperative histological type of tumour, immunohistochemistry, preoperative
histological confirmation of axillary metastasis where available, type of axillary
surgery performed, timing of surgery and the final postoperative histopathology
report.
Laboratory methods Intrinsic subtypes were determined by immunohistochemistry according to the
following criteria as part of the clinical standard at the time of data collection:
Luminal A: Estrogen receptor (ER) and/or Progesterone receptor (PR) positive,
Human epidermal growth factor 2 (HER-2) negative and Ki-67 <15; Luminal B:
ER and/or PR positive, Ki 67≥ 15 or ER and/or PR positive with HER-2 positive;
HER-2 enriched: HER-2 positive alone (ER and PR negative); Triple negative:
ER negative, PR negative, HER-2 negative. 12 Patients were grouped according
to pre-operative and post-operative node status.
Statistical analysis Descriptive statistics was performed reporting percentages for categorical
variables, means and medians for continuous variables. To determine factors
associated with pathological node negative (pN0) ALND, we implemented
univariate and multivariable logistic regression models. All variables that were
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significant at p<0.1 in univariate analysis were evaluated in the multivariate
analysis and non-significant factors were dropped with stepwise backward
regression. A two-sided p-value of <0.05 was considered significant
throughout. A goodness of fit test was carried out on the final model to
determine how well the model fits into the set of variables. All available data
were used for each univariate analysis. In the multivariable analysis, patients
with missing data for included variables were dropped from the model. Analysis
was carried out using Stata version 14 (StataCorp Limited, Texas, United
States of America).
Ethics approval was obtained from the Human Research Ethics Committee
(Medical) of the University of the Witwatersrand prior to the commencement of
this study (MP150549).
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3. RESULTSA total number of 624 patients underwent axillary surgery at CMJAH and
CHBAH breast units from March 2013 to March 2015. We excluded 119
patients according to our predefined criteria and identified 505 eligible patients
for our study (Figure 1). The main reasons for exclusion were recurrent disease
and absence of invasive cancer.
The mean age (±SD) was 53.6 (13.4) years. The majority of patients presented
with clinical stage II (49.3%) and III (37.4%) disease. Most of the patients (480,
95.1%) were diagnosed with ductal carcinoma, 22 patients (4.4%) had lobular
carcinoma and one patient (0.2%) had a mixed type. Two patients (0.4%) had
no information on histological subtype. .The majority of patients (313, 61.9%)
underwent primary surgery and 192 (38.1%) patients had surgery following
neoadjuvant chemotherapy (Table 1).
Table 1: Demographic and clinicopathological characteristics Factors Total N=505 (%)
Age (mean± SD) 53.6 ±13.4
Age group
<40 71 (14.1%)
40-49 139 (27.5%)
50- 59 130 (25.7%)
60-69 98 (19.4%)
≥ 70 67 (13.3%)
Stage (%)
I 46 (9.1%)
II 249 (49.3%)
III 189 (37.4%)
IV 21 (4.2%)
Staging groups
I & II 295 (58.4%)
III & IV 210 (41.6%)
Histological subtype
Ductal 480 (95.0%)
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Lobular 22 (4.4%)
Other 1 (0.2%)
Missing 2 (0.4%)
Immunohistochemistry
Luminal A 87 (17.2%)
Luminal B 303 (60%)
HER-2 enriched 43 (8.5%)
Triple negative 71 (14.1%)
Missing 1 (0.2%)
Clinical nodal staging
cN0 161 (31.9%)
cN+ 344 (68.1%)
Pathological nodal
staging
pN0 199
pN+ 306
Tumour size
Tx 3 (0.6%)
T1 60 (11.9%)
T2 253 (50.1%)
T3 70 (13.9%)
T4 119 (23.6)
Table 2: Comparison of clinical and pathological nodal staging cN1 (%) cN0 (%) Total (%)
pN1 263 (85.9) 43 (14.1) 306 (60.6)
pN0 81 (40.7) 118 (59.3) 199 (39.4)
Total 344 (68.1) 161b(31.9) 505
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Figure 1: Flowchart of axillary surgery
On the basis of clinical examination and ultrasound 344 patients were staged
cN1 (68.1%), 161 (31.9%) were assessed as clinically node negative (cN0) and
were eligible for SLNB. A SLNB was performed in 118 out of these 161 cN0
patients (73.3%). A negative SLNB was found in 102 (86.4%) and a positive
SLNB in 16 (13.6%) patients (Figure 1).
In the cN0 group, 43 patients (26.7%) underwent ALND, 27 (62.8%) had a
positive ALND and 16 (37.2%) had a negative ALND. These patients underwent
ALND for various reasons which include non-availability of tracer or gamma
probe, “large” tumour size (> 4cm) and the surgeon’s clinical decision intra-
operatively to proceed to an ALND.
In the cN1 group, 263 out of the 344 patients (76.4%) had a positive ALND and
81 (23.5%) a negative ALND.
624patientsreceivedaxillarysurgerybetweenmarch2013tomarch2015
N=505
cN1344(68.1%)
ALND344(100%)
Positive263(76.5%)
Negative81(23.5%)
SLNB0(0%)
cN0161(31.9%)
ALND43(26.7%)
Positive27(62.8%)
Negative16(37.2%)
SLNB118(73.3%)
Positive16(13.6%)
Negative102(86.4%)
Totalof119patientswereexcluded48patientshadrecurrentdisease
51patientshadnoinvasivebreastcancer7patientswerenotprimarypresentation
5patientsweremale8patientshadincompletedataonaxillarysurgey
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Overall 306 patients were pN1 (60.6%) and 199 pN0 (39.4%). Overall 387
patients underwent ALND, with a total of 97 (25.1%) of patients having a pN0
ALND. Of the 97 patients, 81 (83.5%) patients were initially assessed as cN1.
Of the 199 pN0 patients, 118 (59.3%) underwent SLNB correctly.
A total of 313 (62%) of 505 patients underwent primary surgery and 192 (38%)
received NACT. After exclusion of patients who had NACT, 169 patients were
staged as cN1 (54%) and 144 (46%) as cN0. (Figure 2) In the cN1 group
undergoing primary surgery, 169 (100%) underwent ALND and 36 (21.3%)
were found pN0. Overall 148 patients were pN0 and 98 (66.2%) underwent
SLNB correctly.
Figure 2: Flowchart of women with invasive breast carcinoma who have primary surgery
The sensitivity, specificity, positive predictive value (PPV) and negative
predictive value (NPV) of pre-op clinical assessment in predicting pathological
status were 85.9%, 59.3%, 76.5% and 73.9%. In patients who had primary
N=313
cN1169(54.0%)
ALND169(100%)
Positive133(78.7%)
Negative36(21.3%)
SLNB0(0%)
cN0144(46.0%)
ALND35(24.3%)
Positive21(60.0%)
Negative14(40.0%)
SLNB109(75.7%)
Positive11(10.1%)
Negative98(89.9%)
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surgery, the sensitivity, specificity, PPV and NPV were 80.6%, 73.9%, 78.7%
and 76.1%. (Table 3)
Table 3: Validity of clinical staging and axillary surgery All patients
N=505 Primary surgery alone (n=303)
Sensitivity 85.9 % 80.6% Specificity 59.3% 73.9% PPV 76.5% 78.7% NPV 73.9% 76.1%
Of the 192 patients who received axillary surgery after NACT, 183 (95.3%)
patients underwent ALND. A total number of 47 (25.7%) of these patients
ultimately had a pN0 ALND. On univariate analysis, patients after NACT of
whom only nine had a SLNB, were not statistically more likely to have a pN0
ALND compared to those patients who underwent primary surgery (OR 1.06,
95% CI: 0.7-1.7, p=0.790).
The factors associated with pN0 at p <0.1 on univariate analysis were: clinical
nodal status and molecular subtype. These variables were further explored in
the multivariate analysis controlling for the first treatment the patient had.
Only 40 (10.4%) out of all patients had a preoperative biopsy or FNA of the
axilla. Patients without preoperative biopsy or FNA of the axilla were also not
found more likely to have a pN0 ALND compared to patients who had pre-
operative biopsy of the axilla, but numbers were small.(OR 1.71, 95% CI: 0.7-
4.0, p=0.195). Triple–negative and HER-2 enriched patients were significantly
more likely to have a pN0 ALND than those with luminal subtypes (OR 3.05,
95% CI: 1.6-5.7, p=0.001 and OR 2.25 , 95% CI: 1.1-4.8, p=0.035). cN0 was
associated with an increased risk compared cN1 (OR 2.10, CI 95%: 1.0-4.3,
p=0.039).
We get a Pearson’s chi-squared goodness of fit value of 6.90 on 9 degree of
freedom with a p-value of 0.6479, and thus no evidence of lack of fit.
Age, tumour size, histological type and pre-op biopsy of the axilla were not
associated with pN0 ALND. (Table 4).
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Table 4: Univariate and multivariate analysis of factors associated with a pN0 ALND
Characteristics Univariate analysis OR (95%CI)
P value Multivariate analysis OR (95%CI)
P value
Age 1.00 (0.99-1.02)
0.467
Age group <40 Reference 0.950 40-49 1.11 (0.5-2.4) 50-59 1.24 (0.6-2.7) 60-69 1.36 (0.6-3.0) ≥70 1.21 (0.5-3.0) T-stage Tx 8.45 (0.7-97.5) 0.267 T1 1.63 (0.5-5.0) T2 1.56 (0.9-2.7) T3 1.61 (0.8-3.2) T4 Reference Clinical nodal status
N0 1.92 (1.0-3.7) 0.054 2.10 (1.0-4.3) 0.039
N1 Reference Clinical staging I & II 1.40 (0.9-2.2) 0.151 IIII & IV Reference Histological type Ductal Reference 0.908 Others 1.06 (0.4-3.0) Molecular subtype Luminal A 1.02 (0.5-2.0) 0.003 1.07 (0.5-2.1) 0.849 Luminal B Reference Reference Reference HER2 enriched 2.05 (1.0-4.3) 2.25 (1.1-4.8)
0.035 Triple negative 2.98 (1.6-5.5) 3.05 (1.6-5.7)
0.001 First Treatment Surgery Reference Neoadjuvant
chemotherapy 1.06 (0.7-1.7) 0.790 1.10 (0.6-1.7) 0.964
Pre-operative biopsy of the axilla
No 1.71 (0.7-4.0) 0.195
Yes Reference **multivariate model built with clinical nodal status, molecular subtype adjusting for first treatment.
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3. DISCUSSION
Of the 505 patients included in our study, 386 (76.6%) underwent ALND and
119 (23.6%) underwent SLNB. A quarter of our patients (97, 25.1%) who
underwent an ALND were ultimately node-negative on pathology. Node
dissection has no oncological benefit in the node-negative patient and is
associated with complications such as lymphoedema. Overtreatment of the
axilla is regarded as obsolete in modern breast cancer surgery and European
guidelines have set the benchmark standards on the proportion of invasive
breast cancer patients with pN0 who did not undergo ALND at a minimum of
80% and the target at 90%. 13 These standards were not reached in our study
cohort with only 66.2% of pN0 patients spared an ALND procedure in those that
received primary surgery, and 59.3% of all pN0 patients spared overall.
The high sensitivity of preoperative assessments to determine clinical nodal
status ultimately show that most of the true nodal positive axillae were operated
on appropriately. Performing an ALND on cN0 patients for various reasons, as
discussed below, can be justified as the majority of these cases (62.8%) were
pN1 ALND’s.
Various factors need to be considered.
Firstly, 81 of the 97 pN0 ALND patients were initially assessed as clinically
node-positive (83.5%). Very few of our patients had pre-operative
histopathological confirmation of nodal involvement and the clinical assessment
in this cohort had a specificity of 59.3% and PPV of 76.5%. NACT may alter the
nodal status but exclusion of patients who received NACT improved these
values only to 73.9% and 78.7%. This highlights the limitations of our
preoperative assessments. We were not able to demonstrate statistical
association with a pN0 ALND outcome without preoperative attempted
pathology confirmation but numbers were small and lacked statistical power.
Negative predictive value of clinical assessment was equally limited at 73.9%
and 76.1% after exclusion of patients who received NACT. Preoperative clinical
assessment needs to be improved to allow for appropriate choice of surgical
axillary approach. A future audit of axillary ultrasounds may assist to improve
the accuracy of preoperative staging of the axilla in our practice.
12
Secondly, ALND was performed in 43 clinically node-negative patients for
various reasons such as large tumour size, intraoperative impression of nodal
involvement or non-availability of a gamma-probe or radio-colloid tracer. In
more than a third of these above mentioned cases (68%); the intra-operative
decision to perform an ALND was correct and in the seven patients where the
decision was taken to proceed to an ALND intra-operatively, the axilla had
nodal involvement in four patients (57%). Although 16 (37.2%) were
pathologically node-negative these clinical decisions to proceed with ALND
need to be viewed in the context of a resource-constrained environment. On
the one hand, the majority (62.8%) were ultimately pN1 and a SLNB would have
potentially required a second surgery to perform a completion ALND. On the
other hand, SLNB should be offered in a well-resourced setting to patients with
large breast cancers and the intraoperative impression of node involvement
confirmed by intraoperative pathology before proceeding to ALND. Under our
circumstances we need to find an appropriate balance to have both a cost
effective and safe policy to manage the axilla in breast cancer.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) Trials B-18
and B-27 demonstrated that NACT can downstage 30-40% of clinically node-
positive patients with no residual disease found in the axilla at the time of
surgery.1415The application of SLNB for initially node-positive patients after
neoadjuvant chemotherapy has been evaluated in the ACOSOG Z1071 and
SENTINA trials. 16 17 A False negative rate (FNR) of under 10% can be
achieved by using a dual-tracer technique and identifying at least three sentinel
nodes.In a recent prospective study 68% of initially pathologically confirmed
node-positive patients became candidates for SLNB after NACT and an ALND
could be avoided in 48%.18 Targeted axillary dissection, after placing clips into
suspicious biopsy proven axillary nodes prior to chemotherapy has been shown
to improve FNR of SLNB after NACT to 4.2%.19 This opens up the possibility
of avoiding ALND after NACT in a subset of our patients. During the study
period, we did not yet apply this approach and the nine patients who underwent
SLNB after NACT were initially cN0.
Complete pathologic response rates vary among intrinsic subtypes and are
reportedly higher in hormone receptor negative tumours.20 We demonstrated a
significantly higher rate of pN0 ALND outcome in the triple-negative and HER-
13
2 enriched subtypes. This could indicate that our preoperative clinical staging
is more accurate in the hormone receptor positive cancers as compared to
HER-2 and triple-negative cancers, and this should be considered when
revising preoperative clinical staging regimens.
47 of 183 patients in this study who received NACT and ALND had a pN0
axillary dissection (25.7%). It must be recognised that most patients did not
have histological or cytological confirmation of axillary involvement before
NACT, and therefore the pre-treatment assessment of the axilla was not in
keeping with international standards. In addition, a pathologic complete
response was found in only 11 cases out of the 192 patients who were operated
following NACT; at 5.7% a rate considerably lower than what would be
expected from the literature.
Clinical staging of this cohort is skewed towards lower stage compared to the
stage at presentation of our general patient population. This is explained by the
inclusion of patients who received axillary surgery in this study. Our units do
not operate on stage 4 disease unless limited to bone metastases or visceral
oligometastases responsive to NACT.
Limitations of this study include the fact that the HIV-status was not recorded
in this study and it is likely to affect clinical assessment of lymph nodes. Benign
lymphadenopathy is often clinically and sonographically misinterpreted as
neoplastic spread. Other limitations of this study include the retrospective
design, the often incomplete nature of clinical records and the relatively small
number of patients.
3. CONCLUSION More than a quarter (25.1%) of axillary node dissections were performed for
pN0 disease in our study population. Pre-operative and intra-operative decision
making for performing ALND’s in cN0 patients is justified, particularly in patients
with suspicious lymph nodes. Where few associated factors for pN0 ALND’s
were found in this study, triple-negative and HER-2 patients had a higher pN0
ALND’s than hormone receptor -positive patients. Our pre-operative nodal
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assessments should be revised to find an appropriate balance that is both cost
effective and safe to manage the axilla in breast cancer.
15
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4. Cubasch H, Joffe M, Hanisch R, et al. Breast cancer
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South Africa. Breast Cancer Res Treat. 2013;140(1):177-186.
doi:10.1007/s10549-013-2606-y
5. Houssami N, Ciatto S, Turner RM, Cody HS, Macaskill P.
Preoperative Ultrasound-Guided Needle Biopsy of Axillary
Nodes in Invasive Breast Cancer. Ann Surg.
2011;254(2):243-251. doi:10.1097/SLA.0b013e31821f1564
6. Mittendorf EA, Hunt KK, Boughey JC, et al. Incorporation of
Sentinel Lymph Node Metastasis Size Into a Nomogram
Predicting Nonsentinel Lymph Node Involvement in Breast
16
Cancer Patients With a Positive Sentinel Lymph Node. Ann
Surg. 2012;255(1):109-115.
doi:10.1097/SLA.0b013e318238f461
7. Yen TWF, Laud PW, Pezzin LE, et al. Prevalence and
consequences of axillary lymph node dissection in the era of
sentinel lymph node biopsy for breast cancer.
doi:10.1097/MLR.0000000000000832
8. Norman SA, Localio AR, Kallan MJ, et al. Risk factors for
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9965.EPI-09-1245
9. Işık A, Grassi A, Soran A. Positive Axilla in Breast Cancer;
Clinical Practice in 2018. Eur J breast Heal. 2018;14(3):134-
135. doi:10.5152/ejbh.2018.4132
10. Krag DN, Anderson SJ, Julian TB, et al. Technical outcomes
of sentinel-lymph-node resection and conventional axillary-
lymph-node dissection in patients with clinically node-
negative breast cancer: results from the NSABP B-32
randomised phase III trial. Lancet Oncol. 2007;8(10):881-888.
doi:10.1016/S1470-2045(07)70278-4
11. NCCN. National Comprehensive Cancer Network. Breast
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subtypes—dealing with the diversity of breast cancer:
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the Primary Therapy of Early Breast Cancer 2011. Ann
Oncol. 2011;22(8):1736-1747. doi:10.1093/annonc/mdr304
13. Rosselli Del Turco M, Ponti A, Bick U, et al. Quality indicators
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17
doi:10.1016/j.ejca.2010.06.119
14. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative
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operable breast cancer: findings from National Surgical
Adjuvant Breast and Bowel Project B-18. J Clin Oncol.
1997;15(7):2483-2493. doi:10.1200/JCO.1997.15.7.2483
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Response of Adding Sequential Preoperative Docetaxel to
Preoperative Doxorubicin and Cyclophosphamide:
Preliminary Results From National Surgical Adjuvant Breast
and Bowel Project Protocol B-27. J Clin Oncol.
2003;21(22):4165-4174. doi:10.1200/JCO.2003.12.005
16. Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel Lymph
Node Surgery After Neoadjuvant Chemotherapy in Patients
With Node-Positive Breast Cancer. JAMA.
2013;310(14):1455. doi:10.1001/jama.2013.278932
17. Kuehn T, Bauerfeind I, Fehm T, et al. Sentinel-lymph-node
biopsy in patients with breast cancer before and after
neoadjuvant chemotherapy (SENTINA): a prospective,
multicentre cohort study. Lancet Oncol. 2013;14(7):609-618.
doi:10.1016/S1470-2045(13)70166-9
18. Mamtani A, Barrio A V., King TA, et al. How Often Does
Neoadjuvant Chemotherapy Avoid Axillary Dissection in
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doi:10.31744/einstein_journal/2019AO3434
19
APPENDIX A – Approved research protocol Axillary Lymph Node Dissection in Invasive Breast Cancer patients at CMJAH and CHBAH
Candidate: Carolette Groenewald MBChB (Pret)
Student number: 1032909
Protocol for MMed (Surg)
Supervisors: Dr Sarah Nietz, MD (Hamburg) MMed (Surg) FCS (SA)
Department of Surgery, University of the Witwatersrand
Breast Unit CMJAH
Dr Herbert Cubasch, Ärztliche Prüfung (München),
FCS(SA)
Department of Surgery, University of the Witwatersrand
Breast Unit CHBAH
Prof Aylwyn Mannell, MBBS BSc(Anat) FRACS (Aust)
FRCS (Engl) MS (Sydney)
Department of Surgery, University of the Witwatersrand
Breast Unit CMJAH
20
Table of Content
1. List of abbreviations ………………………..3
2. Abstract ………………………..3
3. Introduction/background …………………………4-8
4. Study objectives …………………………8
5. Methods …………………………9
6. Data analysis …………………………11
7. Benefit …………………………11
8. Ethics ………………………...11
9. Timing …................................12
10. Cost ………………………..12
11. References ………………………..12-16
12. Appendix A ……………………….17
13. Appendix B ……………………….18-19
21
List of abbreviations
ALND – Axillary Lymph Node Dissection
cN0 – Clinically node negative
cN1 – Clinically node positive
DCIS – Ductal carcinoma in situ
FNR – False negative rate
FNA – Fine needle aspiration
FPR – False positive rate
SLN – Sentinel Lymph Node
SLNB – Sentinel Lymph Node biopsy
22
Abstract The assessment of axillary lymph nodes is a critical step in staging breast
cancer. It predicts prognosis and guides treatment. Physical examination
alone is notoriously inaccurate and suspected axillary involvement should be
confirmed by FNA in cN1 disease or with a SLNB in cN0 axillae. FNA’s are
not routinely done in our resource constrained environment and all patients
with CN1 disease on ultrasound and physical examination, undergo ALND.
Due to the fact that ALND causes significant morbidity, the need for ALND
has been questioned in patients with unproven axillary disease as well as
patients with a complete pathological response after neoadjuvant
chemotherapy.
A retrospective cohort study will be conducted at CMJAH and CHBAH breast
units. Patient records, theatre records and histology results of all female
patients that received axillary surgery during the period March 2013 to March
2015, will be reviewed and data collected in a datasheet.
23
Introduction/Background
The Axilla in Breast Cancer
The axilla receives most of the lymphatic drainage of the breast. Axillary lymph
node involvement in breast cancer correlates with tumor size and location,
lympho vascular invasion, histological grade, as well as patient age and method
of detection (1-4).
Axillary lymph node involvement remains central to the staging of breast cancer
and is considered the single most important prognostic factor in patients with
invasive breast cancer (5,6). Beside the prognostic implications, it guides local,
regional and systemic treatment (7).
Staging of the Axilla
Axillary lymph nodes may appear enlarged clinically and radiologically, which
may be due to causes other than breast cancer. Other malignant causes of
axillary lymphadenopathy include lymphoma, malignant melanoma and lung,
gastric and ovarian carcinomas. Non-malignant causes include various
bacterial and viral infections. Among these, HIV is probably the most important
factor in our setting. Patients with HIV commonly have palpable lymph nodes
and often have bilateral axillary lymphadenopathy on axillary imaging (8).
Several methods are available to evaluate and stage the axilla. These include
non-invasive methods such as physical examination and imaging techniques
including axillary ultrasound, Mammography, PET-CT and MRI. Clinical
evaluation of the axilla by palpation is unfortunately highly inaccurate with an
overall error rate of 41% and a false-positive rate (FPR) of 53%. Axillary
ultrasound combined with needle biopsy has a sensitivity of 79.6 % and a
specificity of 98.3%, PET-CT sensitivity and specificity 56% and 96%,
respectively. MRI has a sensitivity of 88% and specificity 97.3% (9).
The gold standard of definitive evaluation therefore remains pathology.
Historically, this was performed through an axillary lymph node dissection
(ALND) for all breast cancer patients, regardless of their clinical nodal status
24
(10). Nowadays, the sentinel lymph node biopsy (SLNB) has been adopted as
standard of care for clinically node-negative (cN0) patients and ALND in this
patient group has become difficult to justify (11). In a contemporary approach,
a preoperative ultrasound-guided fine needle aspiration (FNA) of a suspicious
lymph node can secure staging in a clinically node-positive (cN1) patient and
identify patients who may proceed directly to ALND rather than SLNB (12). In
cases in which the cytopathology is negative or nondiagnostic, or in clinically
node-negative (cN0) patients, SLNB should be performed for accurate
assessment (5,9).
Axillary Lymph Node Dissection
The surgical management of the axilla in breast cancer patients has
significantly changed since William Halsted performed the first radical
mastectomy in the 19th century (13). ALND served to maximize survival,
achieve regional control and establish the most accurate staging of the axilla
(14). A contemporary standard ALND consists of removal of level I and II nodal
tissue unless level III lymph nodes appear grossly involved (6,15).
ALND is, however, a potentially debilitating procedure with lymphoedema being
the most common serious complication. Norman et al investigated factors
associated with lymphoedema and found that 24.7% of all women diagnosed
with breast cancer experienced mild lymphoedema with 13% reporting severe
debilitating lymphoedema. ALND and anthracycline-based chemotherapy
regimens were the two most important risk factors (16), others include the
presence of positive nodes, the extent of dissection and radiation therapy (17).
Further complications include seroma formation, chronic pain, injury or
thrombosis of axillary vein, nerve injury and shoulder dysfunction (18).
The NSABP B-04 examined women with cN0 invasive breast cancer who were
randomized to radical mastectomy (with ALND), simple mastectomy plus local
nodal irradiation, or simple mastectomy with ALND delayed until positive lymph
nodes developed; the trial found no difference in disease-free or overall survival
rates (19), even on 25-year follow-up (20).
ALND remains the standard of care for node-positive patients but is nowadays
25
regarded as obsolete in the node-negative patient (11).
Sentinel Lymph Node Biopsy
SLNB was developed as an accurate method of staging in node-negative
patients to minimize the anatomic disruption and morbidity of ALND. The
concept is based on the orderly pattern of lymphatic drainage from the primary
tumor of the breast to the regional lymph nodes. The sentinel lymph node (SLN)
is identified as the first lymph node to which the breast and breast cancer will
drain (21).
Multiple studies have validated the use of SLNB as a reliable tool in cN0
patients to obviate more extensive surgery (22). The NSABP B-32 evaluated
whether SLNB can be compared with ALND in terms of survival and regional
control with fewer side effects. They randomly assigned women with invasive
breast cancer to SLNB and ALND or SLNB alone only followed by ALND if the
SLNB was positive. There was no statistical difference between the two groups
in terms of overall survival, disease-free survival and regional control. It was
concluded that SLN surgery alone is safe and adequate in cN0 patients if the
SLN is found to be negative (14).
Although major prospective studies attained false-negative rates (FNR) of 7%
to 10% for SLNB, axillary recurrence occurs in less than 1% of patients with no
metastases in the sentinel node (23,24). This questions the clinical relevance
of low-volume residual disease in the axilla.
SLNB is accepted as standard of care for cN0 early breast cancer and the
indication has been extended to larger (non-inflammatory) tumors, multicentric
tumors, prior breast or axillary surgery and patients with ductal carcinoma in
situ (DCIS) planned for mastectomy (11).
Broadening Application of SLNB to Avoid ALND
Traditionally, breast cancer patients with a positive SLNB were offered
completion ALND (9). A positive SLNB with tumor size >2cm, more than one
positive SLN, lymph node metastasis of ≥2mm, lymph vascular invasion, extra
26
capsular extension and the ratio of involved SLN to uninvolved lymph nodes
predicts the presence of non-sentinel lymph node metastasis (25,26). However,
in over 50% of patients the SLN is the only involved node (27,28).
Two recent trials, including the ACOSOG Z0011 trail, questioned the need for
ALND in patients with a positive SLNB and randomized patients to SLNB alone
and SLNB with completion ALND. Follow up revealed no difference in local or
regional recurrence between the two groups in patients with micro metastases
or less than three involved sentinel nodes. It was concluded that SLNB alone
in selected patients with early breast cancer undergoing breast conserving
therapy with radiation might be an appropriate method of treatment (29,30).
Carette-Weyer et al evaluated the impact of the ACOSOG Z0011 trial results
on clinical practice. They found that widespread implementation of the trial
could spare 38% of patients an ALND (31).
Another evolving area is the use of SLNB following neoadjuvant chemotherapy.
Patients who are cN1 at initial presentation may be downstaged to cN0 in 20-
40% (32,33). Chemotherapy may influence the accuracy of the procedure and
limited data is available. The ACOSOG Z1071 trail found a FNR of 12.6% in
patients who had neoadjuvant chemotherapy followed by SLNB and a
completion ALND dissection (34). In the SENTINA trial, the FNR was 14.2% for
patients who were initially cN1 and converted to a cN0 status after
chemotherapy, but was less than 10% when 3 or more nodes were removed
(7). Both trials indicated that double tracer technique and removing at least
three lymph nodes decreased the FNR. Although not standard of care, the trials
suggest a possibility for SLNB as axilla-conserving surgery in this subgroup of
patients.
Summary And Why Do The Study?
Axillary surgery has evolved from a radical approach to increasingly axilla-
conserving surgery with expanding application of SLNB. ALND carries high
morbidity and is considered obsolete in clinically node-negative patients.
27
cN1 disease should be proven by FNA. Due to resource constraints this has
not been implemented in our units to date and patients deemed node-positive
on physical examination and axillary ultrasound all undergo ALND.
Furthermore, the effect of neoadjuvant chemotherapy with potentially complete
clinical and pathological response in the axillary nodes may offer an opportunity
for axilla-sparing surgery. This has also not been evaluated and initially node-
positive patients all undergo an ALND in our setting.
2. Study Objectives
Primary objective is to evaluate the prevalence of node-negative ALND in our
units. Secondary objective is to evaluate the likelihood of node-negative
dissection both after the administration of neoadjuvant chemotherapy and
where the axilla is found to have clinically node-positive disease without
histological confirmation.
Results may influence future clinical approaches and research projects.
3. Methods
3.1 Study Design
Retrospective cohort study
3.2 Site of study
CMJAH breast unit and CHBAH breast unit
3.3 Study population
All female primary invasive breast cancer patients that underwent axillary
surgery at CMJAH or CHBAH breast units
3.4 Sampling
Subjects will be recruited via theatre records at CMJAH and via the existing
database at CHBAH.
Time period of review will be March 2013-March 2015 (2 years). Estimated
sample size is N= 500.
28
Inclusion criteria:
Women above the age of 18
Histologically proven invasive breast cancer
Breast cancer as primary presentation
Axillary surgery performed
Exclusion criteria:
Recurrent disease
3.5 Study groups and
Patients undergoing ALND will be differentiated in the following groups
- Patients undergoing ALND as part of primary surgery
- Patients undergoing ALND after neoadjuvant chemotherapy
- Patients undergoing ALND with histological or cytological
confirmation of axillary lymphnode metastasis prior to surgery
- Patients undergoing ALND without histological or cytological
confirmation of axillary lymphnode metastasis prior to surgery
3.6 Measuring tool
Histology records and patient records of eligible patients will be reviewed.
Patient records will be accessed via the electronic database at CHBAH and via
breast clinic files at CMJAH.
3.7 Data collection
2 Data sheets will be used to collect data. Data sheet 1 (Appendix A), will
contain identifiable data coded with a study number. This will be kept
confidential. Data sheets will be used to record data for each study number in
Excel. Extracted data is attached in appendix B. All data collected will be used
for demographics.
3.8 Sources of bias:
Incomplete outcome data may be a source of bias. This will be avoided by
thorough review of patient records and accessing further sources of records
29
beyond the breast database and breast clinic files such as the oncology files or
hospital admission records or mammography records.
4. Data Analysis
Data analysis will be performed with Statistica.
Prevalence of node-negative ALND in overall ALND will be calculated.
Clinical assessment without histological confirmation of node-positive disease
and neoadjuvant chemotherapy will be assessed as risk factors for node-
negative ALND. Risk will be assessed by calculation of odds ratios (OR) for
node-negative dissection in the presence of these two risk factors. Confidence
interval (CI) for the odds ratios will be 95%. Significance will be tested by
Fisher’s exact test and chi-squared test.
5. Benefit
Results of the study will indicate how commonly we perform inappropriate
ALND for node-negative disease and the relevance of risk factors. This may
change future clinical approach in our units and guide future research
opportunities.
6. Ethics
Clearance to proceed with the retrospective study will be obtained from the
ethics committee of the University of the Witwatersrand.
7. Time line Jan Feb Mar Apri
l May Jun
e Jul Au
g Sept
Oct Nov Dec
Literature review
x x
Preparing protocol
x x
30
Protocol assessment
x
Ethics application
x
Collecting data
x x x
Data analysis
x x
Writing up - thesis
x x
Writing up - paper
x x
8. Cost
No major expenses are anticipated. The candidate will cover minor expenses
such as photocopying and travel.
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12. Leenders MWH, Broeders M, Croese C, Richir MC, Go HLS, Langenhorst
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al. Ten-year results of a randomized clinical trial comparing radical mastectomy
and total mastectomy with or without radiation. New England Journal of
Medicine 1985;312(11):674-81.
20. Fisher B, Jeong JH, Anderson S, Bryant J, Fisher ER, Wolmark N. Twenty-
five-year follow-up of a randomized trial comparing radical mastectomy, total
mastectomy, and total mastectomy followed by irradiation. N Engl J Med 2002,
Aug 22;347(8):567-75.
21. Straver ME, Meijnen P, van Tienhoven G, van de Velde CJ, Mansel RE,
Bogaerts J, et al. Sentinel node identification rate and nodal involvement in the
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22. Lyman GH, Giuliano AE, Somerfield MR, Benson AB, Bodurka DC, Burstein
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cancer: Results from the NSABP B-32 randomised phase III trial. Lancet Oncol
2007, Oct;8(10):881-8.
25. Mittendorf EA, Hunt KK, Boughey JC, Bassett R, Degnim AC, Harrell R, et
al. Incorporation of sentinel lymph node metastasis size into a nomogram
predicting nonsentinel lymph node involvement in breast cancer patients with a
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33
26. Dauphine CE, Haukoos JS, Vargas MP, Isaac NM, Khalkhali I, Vargas HI.
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35
Appendix A
Identifiable Data sheet 1:
Study nr Patient name Hospital number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
36
Appendix B
Data collection sheet 2:
• Site
o CMJAH
o CHBAH
• Patient information
o Study nr
o Age
• Stage at primary presentation
o T
o N
o M
• Histology preoperative
o Histological type
§ Ductal
§ Lobular
§ Other
o Immunohistochemistry
§ ER
§ PR
§ HER2
§ Ki67
• Preoperative histological confirmation of axillary metastases
o None
37
o FNA/Core biopsy
o SLNB
• Type of axillary surgery
o SLNB
o ALND
o Completion ALND after SLNB
• Timing of Surgery
o Primary Surgery
o Post neoadjuvant chemotherapy
• Histology postoperative
o SLNB
§ Nr of SLN removed
§ Nr of positive SLN
o ALND
§ Nr of LN removed
§ Nr of LN involved
o Completion ALND
§ Nr of LN removed
§ Nr of LN involved
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APPENDIX B – Protocol assessment form
39
40
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Appendix C - Ethics approval
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APPENDIX D – Supervisor Declaration 28 March 2017 Attention: Faculty of Health Sciences, University of Witwatersrand Re: Axillary lymph node dissection in invasive breast cancer patients at Charlotte Maxeke Johannesburg Academic Hospital and Chris Hani Baragwanath Academic Hospital This letter serves to certify that Carolette Groenewald is the primary author of the above-entitled research. It has been submitted to the South African Journal of Science. It is sufficient for consideration as a published paper towards the research component of his Mmed degree at the University of Witwatersrand. Her contribution to the research was as follows:
• Protocol write-up, submission and presentation at the Faculty of Health Sciences • Ethics application • Collection of data, entry into relevant processing programs and data analysis • Research write-up • Formatting for submission to the journal • Communication with the journal editor and refining review points
As supervisors of the research project, we reviewed the research at regular intervals, made changes to improve the write-up and verified the data analysis. We agree that the research was the work of Carolette Groenewald, assisted and refined by us. ……………………………. SL [email protected] ……………………………… H Cubasch [email protected] ……………………………. A Mannell [email protected]
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APPENDIX E - Identifiable data sheet 1 Identifiable Data sheet 1:
Study nr Patient name Hospital number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
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APPENDIX F – Data collection sheet 2 Data collection sheet 2:
• Site
o CMJAH
o CHBAH
• Patient information
o Study nr
o Age
• Stage at primary presentation
o T
o N
o M
• Histology preoperative
o Histological type
§ Ductal
§ Lobular
§ Other
o Immunohistochemistry
§ ER
§ PR
§ HER2
§ Ki67
• Preoperative histological confirmation of axillary metastases
o None
o FNA/Core biopsy
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o SLNB
• Type of axillary surgery
o SLNB
o ALND
o Completion ALND after SLNB
• Timing of Surgery
o Primary Surgery
o Post neoadjuvant chemotherapy
• Histology postoperative
o SLNB
§ Nr of SLN removed
§ Nr of positive SLN
o ALND
§ Nr of LN removed
§ Nr of LN involved
o Completion ALND
§ Nr of LN removed
§ Nr of LN involved
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APPENDIX G – SAJS GUIDELINES TO AUTHORS South African Journal of Surgery Author Guidelines
Author Guidelines Accepted manuscripts that are not in the correct format specified in these guidelines will be returned to the author(s) for correction, and will delay publication. AUTHORSHIP Named authors must consent to publication. Authorship should be based on substantial contribution to: (i) conception, design, analysis and interpretation of data; (ii) drafting or critical revision for important intellectual content; and (iii) approval of the version to be published. These conditions must all be met (uniform requirements for manuscripts submitted to biomedical journals; refer to www.icmje.org). CONFLICT OF INTEREST Authors must declare all sources of support for the research and any association with a product or subject that may constitute conflict of interest. RESEARCH ETHICS COMMITTEE APPROVAL Provide evidence of Research Ethics Committee approval of the research where relevant. PROTECTION OF PATIENT'S RIGHTS TO PRIVACY Identifying information should not be published in written descriptions, photographs, and pedigrees unless the information is essential for scientific purposes and the patient (or parent or guardian) gives informed written consent for publication. The patient should be shown the manuscript to be published. Refer to www.icmje.org. ETHNIC CLASSIFICATION References to ethnic classification must indicate the rationale for this. MANUSCRIPTS Shorter items are more likely to be accepted for publication, owing to space constraints and reader preferences. Original articles not exceeding 3 000 words, with up to 6 tables or illustrations, are usually observations or research of relevance to surgery. References should preferably be limited to no more than 15. Please provide a structured abstract not exceeding 250 words, with the following recommended headings: Background, Objectives, Methods, Results, and Conclusion. Scientific letters/short reports, which include case reports, side effects of drugs and brief or negative research findings should preferably be 1500 words or less, with 1 table or illustration and no more than 6 references. Please provide an accompanying abstract not exceeding 150 words. Editorials, Opinions, etc. should be about 1000 words and are welcome, but unless invited, will be subjected to the SAJS peer review process. Review articles are rarely accepted unless invited. Letters to the editor, for publication, should be about 400 words with only one illustration or table, and must include a correspondence address.
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Obituaries should be about 400 words and may be accompanied by a photograph. MANUSCRIPT PREPARATION Refer to articles in recent issues for the presentation of headings and subheadings. If in doubt, refer to 'uniform requirements' - www.icmje.org. Manuscripts must be provided in UK English. Qualification, affiliation and contact details of ALL authors must be provided in the manuscript and in the online submission process. Abbreviations should be spelt out when first used and thereafter used consistently, e.g. 'intravenous (IV)' or 'Department of Health (DoH)'. Scientific measurements must be expressed in SI units except: blood pressure (mmHg) and haemoglobin (g/dl). Litres is denoted with a lowercase 'l' e.g. 'ml' for millilitres). Units should be preceded by a space (except for %), e.g. '40 kg' and '20 cm' but '50%'. Greater/smaller than signs (> and 40 years of age'. The same applies to ± and º, i.e. '35±6' and '19ºC'. Numbers should be written as grouped per thousand-units, i.e. 4 000, 22 160... Quotes should be placed in single quotation marks: i.e. The respondent stated: '...' Round brackets (parentheses) should be used, as opposed to square brackets, which are reserved for denoting concentrations or insertions in direct quotes. General formatting The manuscript must be in Microsoft Word or RTF document format. Text must be single-spaced, in 12-point Times New Roman font, and contain no unnecessary formatting (such as text in boxes, with the exception of Tables). ILLUSTRATIONS AND TABLES If tables or illustrations submitted have been published elsewhere, the author(s) should provide consent to republication obtained from the copyright holder. Tables may be embedded in the manuscript file or provided as 'supplementary files'. They must be numbered in Arabic numerals (1,2,3...) and referred to consecutively in the text (e.g. 'Table 1'). Tables should be constructed carefully and simply for intelligible data representation. Unnecessarily complicated tables are strongly discouraged. Tables must be cell-based (i.e. not constructed with text boxes or tabs), and accompanied by a concise title and column headings. Footnotes must be indicated with consecutive use of the following symbols: * † ‡ § ¶ || then ** †† ‡‡ etc. Figures must be numbered in Arabic numerals and referred to in the text e.g. '(Fig. 1)'. Figure legends: Fig. 1. 'Title...' All illustrations/figures/graphs must be of high resolution/quality: 300 dpi or more is preferable but images must not be resized to increase resolution. Unformatted and uncompressed images must be attached as 'supplementary files' upon submission (not embedded in the accompanying manuscript). TIFF and PNG formats are preferable; JPEG and PDF formats are accepted, but authors must be wary of image compression. Illustrations and graphs prepared in Microsoft Powerpoint or Excel must be accompanied by the original workbook. REFERENCES Authors must verify references from the original sources. Only complete, correctly formatted reference lists will be accepted. Reference lists must be generated manually and not with the use of reference manager software. Citations should be inserted in the
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text as superscript numbers between square brackets, e.g. These regulations are endorsed by the World Health Organization,[2] and others.[3,4-6] All references should be listed at the end of the article in numerical order of appearance in the Vancouver style (not alphabetical order). Approved abbreviations of journal titles must be used; see the List of Journals in Index Medicus. Names and initials of all authors should be given; if there are more than six authors, the first three names should be given followed by et al. First and last page, volume and issue numbers should be given. Wherever possible, references must be accompanied by a digital object identifier (DOI) link and PubMed ID (PMID)/PubMed Central ID (PMCID). Authors are encouraged to use the DOI lookup service offered by CrossRef. Journal references: Price NC, Jacobs NN, Roberts DA, et al. Importance of asking about glaucoma. Stat Med 1998;289(1):350-355. [http://dx.doi.org/10.1000/hgjr.182] [PMID: 2764753] Book references: Jeffcoate N. Principles of Gynaecology. 4th ed. London: Butterworth, 1975:96-101. Chapter/section in a book: Weinstein L, Swartz MN. Pathogenic Properties of Invading Microorganisms. In: Sodeman WA jun, Sodeman WA, eds. Pathologic Physiology: Mechanisms of Disease. Philadelphia: WB Saunders, 1974:457-472. Internet references: World Health Organization. The World Health Report 2002 - Reducing Risks, Promoting Healthy Life. Geneva: World Health Organization, 2002. http://www.who.int/whr/2002 (accessed 16 January 2010). Other references (e.g. reports) should follow the same format: Author(s). Title. Publisher place: publisher name, year; pages. Cited manuscripts that have been accepted but not yet published can be included as references followed by '(in press)'. Unpublished observations and personal communications in the text must not appear in the reference list. The full name of the source person must be provided for personal communications e.g. '...(Prof. Michael Jones, personal communication)'. PROOFS A PDF proof of an article may be sent to the corresponding author before publication to resolve remaining queries. At that stage, only typographical changes are permitted; the corresponding author is required, having conferred with his/her co-authors, to reply within 2 working days in order for the article to be published in the issue for which it has been scheduled. CHANGES OF ADDRESS Please notify the Editorial Department of any contact detail changes, including email, to facilitate communication. CPD POINTS Authors can earn up to 15 CPD CEUs for published articles. Certificates may be requested after publication of the article. CHARGES There is no charge for the publication of manuscripts.
Submission Preparation Checklist As part of the submission process, authors are required to check off their submission's compliance with all of the following items, and submissions may be returned to authors that do not adhere to these guidelines. 1 Named authors consent to publication and meet the requirements of
authorship as set out by the journal. 2 The submission has not been previously published, nor is it before
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another journal for consideration. 3 The text complies with the stylistic and bibliographic requirements
in Author Guidelines. 4 The manuscript is in Microsoft Word or RTF document format. The text
is single-spaced, in 12-point Times New Roman font, and contains no unnecessary formatting.
5 Illustrations/figures are high resolution/quality (not compressed) and in an acceptable format (preferably TIFF or PNG). These must be submitted as 'supplementary files' (not in the manuscript).
6 For illustrations/figures or tables that have been published elsewhere, the author has obtained written consent to republication from the copyright holder.
7 Where possible, references are accompanied by a digital object identifier (DOI) and PubMed ID (PMID)/PubMed Central ID (PMCID).
8 An abstract has been included where applicable. 9 The research was approved by a Research Ethics Committee (if
applicable) 10 Any conflict of interest (or competing interests) is indicated by the
author(s).
Copyright Notice The South African Journal of Surgery (SAJS) reserves copyright of the material published. The work is licensed under a Creative Commons Attribution - Noncommercial Works License. Material submitted for publication in the SAJS is accepted provided it has not been published elsewhere. The SAJS does not hold itself responsible for statements made by the authors.
Privacy Statement The SAJS is committed to protecting the privacy of the users of this journal website. The names, personal particulars and email addresses entered in this website will be used only for the stated purposes of this journal and will not be made available to third parties without the user’s permission or due process. Users consent to receive communication from the SAJS for the stated purposes of the journal. Queries with regard to privacy may be directed to [email protected]. South African Journal of Surgery | Online ISSN: 2078-5151 | Print ISSN: 0038-2361 | Medpharm Publications